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Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients.

Park SH, Noh SJ, Kim KM, Bae JS, Kwon KS, Jung SH, Kim JR, Lee H, Chung MJ, Moon WS, Kang MJ, Jang KY - Transl Oncol (2015)

Bottom Line: In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph) was an additional independent prognostic predictor for OS (P < .001) and RFS (P < .001).The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1) subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4) subgroup.This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.

No MeSH data available.


Related in: MedlinePlus

The prognostic significance of the cytoplasmic expression of BRCA1 and BRCA2 in 192 BCAs. (A) The receiver operating characteristic curve analysis for the determination of cutoff points for the immunohistochemical staining scores of the cytoplasmic expression of BRCA1 (cBRCA1) and BRCA2 (cBRCA2). The cutoff points were determined at the highest area under the curve value representing the highest positive likelihood point for the estimation of the death of patients. The arrowhead indicates the cutoff point for cBRCA1, and the arrow indicates the cutoff point for cBRCA2. Cases with scores equal or greater than 10 for cBRCA1 expression were considered positive. The cBRCA2 expression was considered positive when the scores were equal or greater than 7. (B) Kaplan-Meier survival analysis for the OS and RFS according to cBRCA1 and cBRCA2 expression.
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f0020: The prognostic significance of the cytoplasmic expression of BRCA1 and BRCA2 in 192 BCAs. (A) The receiver operating characteristic curve analysis for the determination of cutoff points for the immunohistochemical staining scores of the cytoplasmic expression of BRCA1 (cBRCA1) and BRCA2 (cBRCA2). The cutoff points were determined at the highest area under the curve value representing the highest positive likelihood point for the estimation of the death of patients. The arrowhead indicates the cutoff point for cBRCA1, and the arrow indicates the cutoff point for cBRCA2. Cases with scores equal or greater than 10 for cBRCA1 expression were considered positive. The cBRCA2 expression was considered positive when the scores were equal or greater than 7. (B) Kaplan-Meier survival analysis for the OS and RFS according to cBRCA1 and cBRCA2 expression.

Mentions: Concerning the prognostic impact of BRCA1 and BRCA2 expression status, our results have shown that the loss of immunohistochemical expression of BRCA1 and BRCA2 is associated with favorable prognosis. However, the prognostic impact of BRCA1/2 expression status has been debated in the literature. Earlier reports showed that BRCA1/2-related BCA had a favorable prognosis [43]; however, poor prognosis in BRCA1/2-mutated BCA patients has also been reported [44] and there were no prognostic differences between BRCA1-related BCA and BRCA1-unrelated BCA in other reports [45,46]. The 10-year survival rates for carriers of the BRCA1 mutation and non-carriers were reported as 80.9% and 82.2%, respectively [46]. However, in our study, immunohistochemical expression of both BRCA1 and BRCA2 was significantly associated with shorter OS and RFS. The 10-year OS rates were 90%, 91%, 70%, and 62% in the BRCA1−, BRCA2−, BRCA1+, and BRCA2+ subgroups, respectively. Similarly, a recent report has shown that immunohistochemical expression of nuclear BRCA1 is associated with poor survival of BCA [37] and ovarian serous carcinomas [47]. However, when considering the role of BRCA1/2 as a potent tumor suppressor, the poor prognosis in BRCA1/2-expressing BCA patients is paradoxical. This finding might be related with the fact that BRCA1/2-defective cells are more sensitive to chemotherapeutic agents. In ovarian carcinomas, BRCA1/2 defectiveness was related with platinum resistance [48–50]. In our study, nuclear expression of BRCA1 and BRCA2 was associated with shorter survival in the subgroup of BCA patients who received adjuvant chemotherapy. Therefore, it is suggested that BRCA-ness is associated with chemoresistance. In addition to the nuclear expression of BRCA1, it has been suggested that cytoplasmic expression of BRCA1 is representative of mutant BRCA1 [51]. Therefore, we separately analyzed the cytoplasmic expression of BRCA1/2 and expected that the result might be opposite to the result from the nuclear expression of BRCA1. However, cytoplasmic expression of BRCA1 and BRCA2 was also significantly associated with shorter OS (log-rank, BRCA1, P < .001; BRCA2, P < .001) and RFS (log-rank, BRCA1, P < .001; BRCA2, P < .001; Figure S1). These findings suggest that generalized expression levels of BRCA1/2 might influence the progression of BCA and/or response to the chemotherapy, but further studies are needed to clarify the role of BRCA1/2 according to its intracellular localization.


Expression of DNA Damage Response Molecules PARP1, γH2AX, BRCA1, and BRCA2 Predicts Poor Survival of Breast Carcinoma Patients.

Park SH, Noh SJ, Kim KM, Bae JS, Kwon KS, Jung SH, Kim JR, Lee H, Chung MJ, Moon WS, Kang MJ, Jang KY - Transl Oncol (2015)

The prognostic significance of the cytoplasmic expression of BRCA1 and BRCA2 in 192 BCAs. (A) The receiver operating characteristic curve analysis for the determination of cutoff points for the immunohistochemical staining scores of the cytoplasmic expression of BRCA1 (cBRCA1) and BRCA2 (cBRCA2). The cutoff points were determined at the highest area under the curve value representing the highest positive likelihood point for the estimation of the death of patients. The arrowhead indicates the cutoff point for cBRCA1, and the arrow indicates the cutoff point for cBRCA2. Cases with scores equal or greater than 10 for cBRCA1 expression were considered positive. The cBRCA2 expression was considered positive when the scores were equal or greater than 7. (B) Kaplan-Meier survival analysis for the OS and RFS according to cBRCA1 and cBRCA2 expression.
© Copyright Policy - CC BY-NC-ND
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4562981&req=5

f0020: The prognostic significance of the cytoplasmic expression of BRCA1 and BRCA2 in 192 BCAs. (A) The receiver operating characteristic curve analysis for the determination of cutoff points for the immunohistochemical staining scores of the cytoplasmic expression of BRCA1 (cBRCA1) and BRCA2 (cBRCA2). The cutoff points were determined at the highest area under the curve value representing the highest positive likelihood point for the estimation of the death of patients. The arrowhead indicates the cutoff point for cBRCA1, and the arrow indicates the cutoff point for cBRCA2. Cases with scores equal or greater than 10 for cBRCA1 expression were considered positive. The cBRCA2 expression was considered positive when the scores were equal or greater than 7. (B) Kaplan-Meier survival analysis for the OS and RFS according to cBRCA1 and cBRCA2 expression.
Mentions: Concerning the prognostic impact of BRCA1 and BRCA2 expression status, our results have shown that the loss of immunohistochemical expression of BRCA1 and BRCA2 is associated with favorable prognosis. However, the prognostic impact of BRCA1/2 expression status has been debated in the literature. Earlier reports showed that BRCA1/2-related BCA had a favorable prognosis [43]; however, poor prognosis in BRCA1/2-mutated BCA patients has also been reported [44] and there were no prognostic differences between BRCA1-related BCA and BRCA1-unrelated BCA in other reports [45,46]. The 10-year survival rates for carriers of the BRCA1 mutation and non-carriers were reported as 80.9% and 82.2%, respectively [46]. However, in our study, immunohistochemical expression of both BRCA1 and BRCA2 was significantly associated with shorter OS and RFS. The 10-year OS rates were 90%, 91%, 70%, and 62% in the BRCA1−, BRCA2−, BRCA1+, and BRCA2+ subgroups, respectively. Similarly, a recent report has shown that immunohistochemical expression of nuclear BRCA1 is associated with poor survival of BCA [37] and ovarian serous carcinomas [47]. However, when considering the role of BRCA1/2 as a potent tumor suppressor, the poor prognosis in BRCA1/2-expressing BCA patients is paradoxical. This finding might be related with the fact that BRCA1/2-defective cells are more sensitive to chemotherapeutic agents. In ovarian carcinomas, BRCA1/2 defectiveness was related with platinum resistance [48–50]. In our study, nuclear expression of BRCA1 and BRCA2 was associated with shorter survival in the subgroup of BCA patients who received adjuvant chemotherapy. Therefore, it is suggested that BRCA-ness is associated with chemoresistance. In addition to the nuclear expression of BRCA1, it has been suggested that cytoplasmic expression of BRCA1 is representative of mutant BRCA1 [51]. Therefore, we separately analyzed the cytoplasmic expression of BRCA1/2 and expected that the result might be opposite to the result from the nuclear expression of BRCA1. However, cytoplasmic expression of BRCA1 and BRCA2 was also significantly associated with shorter OS (log-rank, BRCA1, P < .001; BRCA2, P < .001) and RFS (log-rank, BRCA1, P < .001; BRCA2, P < .001; Figure S1). These findings suggest that generalized expression levels of BRCA1/2 might influence the progression of BCA and/or response to the chemotherapy, but further studies are needed to clarify the role of BRCA1/2 according to its intracellular localization.

Bottom Line: In addition, the combined expressional pattern of BRCA1, BRCA2, PARP1, and γH2AX (CSbbph) was an additional independent prognostic predictor for OS (P < .001) and RFS (P < .001).The 10-year OS rate was 95% in the CSbbph-low (CSbbph scores 0 and 1) subgroup, but that was only 35% in the CSbbph-high (CSbbph score 4) subgroup.This study has demonstrated that the individual and combined expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 could be helpful in determining an accurate prognosis for BCA patients and for the selection of BCA patients who could potentially benefit from anti-PARP1 therapy with a combination of genotoxic chemotherapeutic agents.

View Article: PubMed Central - PubMed

Affiliation: Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Stanford University School of Medicine, Stanford, CA, USA.

No MeSH data available.


Related in: MedlinePlus